The overall goal of this project is to identify all of the genetic elements within the MHC that predispose to rheumatoid arthritis (RA). Preliminary data from the PI and others indicates that at least two regions outside of the DRB1 locus contain risk genes for RA. One of these regions lies in the central MHC and is likely to reflect the presence of polymorphisms that are present on a common extended haplotype found in white populations, the A1-B8-DR3 ("8.1") haplotype. A second risk region appears to be located in the MHC class I region, and may contribute to the very high relative risk (RR) associated with certain compound heterozygote genotypes such as DRB1*0401/0404. In specific aim 1 we will confirm and extend these observations by carrying out a dense SNP scan of the MHC on an initial set of 1,500 RA cases and 1,500 matched controls from the Swedish population. In specific aim 2, we will replicate the findings in specific aim 1, and narrow the risk regions further using dense association mapping. These studies will draw on a set of approximately 6,000 RA patients and controls from the U.S. populations, as well as an additional 1500 RA cases and matched controls from Sweden. Finally, in specific aim 3, we will search for genetic interactions between the genes identified within the MHC, including the DRB1 locus, and risk genes found outside the MHC. These studies will initially focus on the C2ta/MHC2TA gene on chromosome 16. This gene is a transcriptional regulator of HLA gene expression, and polymorphisms of this gene have recently been shown to influence MHC class II expression in the rat in response to injury and inflammation. Furthermore, preliminary data indicate an association of a C2ta regulatory SNP with rheumatoid arthritis and other inflammatory disorders. Thus, in specific aim 3 we will specifically investigate whether interactive genetic effects can be observed between C2ta and any of the risk regions within the MHC that are identified in specific aims 1 and 2. Since multiple non-MHC genes, as well as environmental factors, are likely to contribute to RA susceptibility, the precise delineation of the genetic risk factors within the MHC will facilitate investigation of additional interactive effects in the future.